tbuckley/cabot-search huggingface dataset:
LB0008 Novel pathogenetic mechanisms mediated by dysregulation of TRIM21-STING-type I interferon axis in lupus
Authors: H. W. Park, D. S. Kim, Y. Park, M. L. Cho, S. K. Kwok
Journal: Annals of the Rheumatic Diseases (2023)

<h3>Background</h3> Tripartite motif-containing protein (TRIM) 21 is an E3 uniquitin-protein ligase, involved in the ubiquitin-dependent proteolysis pathway of various proteins including factors related to type I interferon pathways. Although the presence of autoantibodies against TRIM21 in various autoimmune diseases suggests potential pathogenetic roles, no studies have clarified its exact implications especially in lupus. <h3>Objectives</h3> We aimed to elucidate the functions of TRIM21 in dysregulation of type I interferon signals in lupus. <h3>Methods</h3> To investigate effects of TRIM21 dysfunction in lupus pathogenesis, two independent lupus animal models, the R848-induced model and the B6/<i>lpr</i> mice model were performed using TRIM21 knockout mice and their phenotypes and immunological profiles were determined. In addition, we investigated the degree of TRIM21 dysfunction and therapeutic effects of <i>in vivo</i> delivery of TRIM21 in MRL/<i>lpr</i> mice. To evaluate the E3 ubiquitin ligase activity of TRIM21 for targeted proteins in type I interferon pathways, we performed specialized immunoblot assay. <h3>Results</h3> The R848-induced model and the B6/<i>lpr</i> model both presented with more severe lupus-like phenotypes such as nephritis, lymphadenopathies, and inflammatory immune cell profiles in TRIM21 knockout mice than in control mice. TRIM21 deficiency resulted in activation of intracellular factors related to type I interferon pathways such as STING, TBK1, and IRF3 in both models. MRL/<i>lpr</i> mice presented with activation of type I interferon pathways including STING, TBK1, and IRF3, and decreased expressions of TRIM21. Overexpression of TRIM21 attenuated the disease phenotypes in MRL/<i>lpr</i> mice. Using immunoblot assay, we observed E3 ubiquitin ligase activity of TRIM21 directly targeting STING via the proteasome pathway. (A) Bodyweight changes of R848- or vehicle-treated mice. (B) Representative images of H&amp;E-stained kidney tissues from R848- or vehicle-treated mice. (C) Glomerular score, tubular damage score, and perivascular pathology score of kidney tissues from R848- or vehicle-treated mice. (D) Percentages of interferon-gamma-positive or IL-4-positive CD4+ T cells from R848- or vehicle-treated mice. <h3>Conclusion</h3> TRIM21 dysfunction induced dysregulation of STING-type I interferon pathways and exacerbates the disease in lupus animal models. Targeting TRIM21-STING-type I interferon axis can be a novel therapeutic strategy in lupus treatment. <h3>References</h3> <b>NIL</b>. <h3>Acknowledgements</h3> <b>NIL</b>. <h3>Disclosure of Interests</h3> None Declared.
POS0264 PALMITOYLETHANOLAMIDE (PEA) AND ACETYL-L-CARNITINE (ALC) ACT SYNERGISTICALLY WITH DULOXETINE AND PREGABALIN IN FIBROMYALGIA: PROSPECTIVE AND RETROSPECTIVE ANALYSES
Authors: F. Salaffi, S. Farah, V. Giorgi, P. Sarzi-Puttini, M. DI Carlo
Journal: Annals of the Rheumatic Diseases (2023)

<h3>Background</h3> Fibromyalgia (FM) is characterized by debilitating pain that is unresponsive to standard analgesics and the multi-modal approach, including drugs' combination, represents the standard of care. Combination therapeutic strategies also include the integration of drugs and nutraceuticals. Both palmitoylethanolamide (PEA) and acetyl-L-carnitine (ALC) have demonstrated an effect on chronic widespread pain (CWP). <h3>Objectives</h3> The aim of this study was to evaluate the efficacy of pregabalin (PGB) and duloxetine (DLX) supplemented with palmitoylethanolamide (PEA) and acetyl-L-carnitine (ALC) in FM patients over a 24-week period. <h3>Methods</h3> After 6 months of stable treatment with DLX+PGB, FM patients were randomized to continue the treatment (Group 1) or to add PEA (600 mg BID)+ALC (500 mg BID) at the ongoing treatment (Group 2). Patients were then followed for 24 weeks. Cumulative disease severity, estimated using the Widespread Pain Index (WPI) (primary outcome), the revised Fibromyalgia Impact Questionnaire (FIQR), and the modified Fibromyalgia Assessment Status (FASmod) (secondary outcomes), was calculated every two weeks during the 24-week follow-up and expressed as time-integrated values (AUC). <h3>Results</h3> One hundred and forty-two FM patients started the study (91.5%), 130 completed both steps, respectively 68 patients in Group 1 and 62 in Group 2. After 24 weeks of follow-up after randomization, Group 2 experienced an adjunctive significant improvement in WPI, FIQR (Figure 1), and FASmod, compared to Group 1. Although there was some fluctuation in both Groups throughout the study period, the AUC values of the WPI scores steadily decreased in Group 2 (p=0.048). Group 2 showed better outcomes also in terms of FIQR and FASmod scores' AUC values (p=0.033 and p=0.017, respectively). <h3>Conclusion</h3> This study supports the supplementary value of PEA+ALC in FM patients care and, to best of our knowledge, it is the first study investigating this association treatment. <h3>References</h3> [1]Sarzi-Puttini P et al. Acetyl-L-carnitine in chronic pain: A narrative review. Pharmacol Res 2021; 173: 105874. https://doi.org/10.1016/j.phrs.2021.105874 [2]Del Giorno R et al. Palmitoylethanolamide in Fibromyalgia: Results from Prospective and Retrospective Observational Studies. Pain Ther 2015; 4: 169-178. https://doi.org/10.1007/s40122-015-0038-6 <h3>Acknowledgements:</h3> NIL. <h3>Disclosure of Interests</h3> None Declared.
POS0087 ADHERENCE TO EULAR SERUM URATE MONITORING GUIDELINES AMONGST OLDER ADULTS WITH GOUT IN ONTARIO, CANADA: A POPULATION-BASED STUDY
Authors: T. Kwok, B. Kuriya, G. A. Hawker, P. LI, G. Choy, J. Widdifield
Journal: Annals of the Rheumatic Diseases (2023)

<h3>Background</h3> Serum urate (SUA) monitoring plays an important role in the treat-to-target recommendations of gout. Adherence to SUA monitoring recommendations after initiation of urate lowering therapy (ULT) is unknown. <h3>Objectives</h3> We assessed the proportion of older adults with gout undergoing SUA testing 6-months after ULT initiation and associated patient and physician-level factors. <h3>Methods</h3> This population-based retrospective cohort study identified patients aged ≥ 66 with gout and newly dispensed ULT between January 1, 2010 and March 31, 2019 from physician billing and pharmacy claims data in Ontario, Canada. We characterized the proportion of patients that received SUA testing within 6-months after ULT dispensation. Multi-level logistic regression clustered by ULT prescriber evaluated factors associated with SUA monitoring by 6-months including patient, prescriber characteristics, prescription information and healthcare usage factors. <h3>Results</h3> 44,438 patients with mean (SD) age of 76.0 (7.3) years and 64.4% males were included. Family physicians prescribed 79.1% of all ULTs. SUA testing was lowest in 2010 at 56.4% and rose over time to 71.3% in 2019 (p &lt;0.0001). By 2019, SUA monitoring was highest amongst rheumatologists (93.9%) and lowest amongst family physicians (67.4%) (Figure 1). Compared with rheumatologists, family physicians (OR 0.26, 95% CI: 0.23–0.29), internists (OR 0.34, 95% CI: 0.29–0.39), nephrologists (OR 0.37, 95% CI: 0.30–0.45) and other specialties (OR 0.25, 95% CI: 0.21–0.29) were less likely to test SUA, as were male physicians (OR 0.87, 95% CI: 0.83–0.91). Patient factors associated with lower odds of SUA monitoring included: rural residence (OR 0.81, 95% CI: 0.77–0.86), lower socioeconomic status (OR 0.91, 95% CI: 0.85–0.97) and patient comorbidities. Correlates of SUA monitoring included: chronic kidney disease (OR 1.40, 95% CI: 1.32–1.49) hypertension (OR 1.11, 95% CI: 1.04–1.18), diabetes (OR 1.17, 95% CI: 1.12–1.22) and co-prescription of colchicine/oral corticosteroids (OR 1.31, 95% CI: 1.23–1.40) (Table 1). <h3>Conclusion</h3> While most gout patients under rheumatology care were adherent to EULAR monitoring recommendations, at the population-level, SUA monitoring is suboptimal amongst older adults with gout initiating ULT but improving over time. ULT prescriber, patient and prescription characteristics affected SUA monitoring. These findings suggest care variations and the need to mobilize quality improvement activities in chronic gout management. <h3>REFERENCES:</h3> NIL. <h3>Acknowledgements:</h3> NIL. <h3>Disclosure of Interests</h3> None Declared.
POS0001 A NOVEL METHOTREXATE TARGET TP63 SUPPRESSES FOXP3 EXPRESSION AND EXACERBATES AUTOIMMUNE ARTHRITIS
Authors: K. Suga, A. Suto, S. Tanaka, T. Kageyama, J. Ishikawa, A. Iwata, S. Furuta, K. Ikeda, K. Suzuki, H. Nakajima
Journal: Annals of the Rheumatic Diseases (2023)

<h3>Background</h3> Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease characterized by autoreactive T cell activity and the presence of autoantibodies [1]. Although methotrexate (MTX) is well-recognized as the "anchor drug" for the treatment of RA [2], its precise mechanism, except antifolate activity, is largely unknown. <h3>Objectives</h3> The aim of this study was to elucidate a molecular target of MTX and to determine the role of the target molecule in CD4<sup>+</sup> T cells. <h3>Methods</h3> We examined comprehensive gene expression profiles of CD4<sup>+</sup> T cells by DNA microarray before and after MTX treatment in RA patients. We also examined the role of Tp63, a possible target of MTX, in human/mouse CD4<sup>+</sup> T cells. <h3>Results</h3> TP63 was the most significantly downregulated gene in CD4<sup>+</sup> T cells of RA patients after MTX treatment. TAp63, an isoform of Tp63, was highly expressed in human/mouse Th17 cells but rarely expressed in Treg cells, and MTX suppressed its expression in vitro. By comparing the comprehensive gene expression profiles between human Th17 cells overexpressing TAp63α and those with TAp63 knockdown, Foxp3 was identified as one of the downregulated genes by TAp63. Reporter assays revealed that TAp63α suppressed the activation of the Foxp3 CNS2 enhancer. TAp63 knockdown in induced-Tregs promoted Foxp3 CNS2 hypomethylation and enhanced suppressive activity of induced-Tregs. Moreover, the severity of arthritis was ameliorated in SCID mice transferred with SKG CD4<sup>+</sup> T cells with TAp63 knockdown compared to those with non-silencing. <h3>Conclusion</h3> TAp63 suppresses Foxp3 expression and exacerbates autoimmune arthritis. <h3>References</h3> [1]Klareskog L, et al. Immunity to citrullinated proteins in rheumatoid arthritis. <i>Annu Rev Immunol.</i> 2008;26:651-75. [2]Cronstein BN, and Aune TM. Methotrexate and its mechanisms of action in inflammatory arthritis. <i>Nat Rev Rheumatol.</i> 2020;16(3):145-54. <h3>Acknowledgements:</h3> NIL. <h3>Disclosure of Interests</h3> None Declared.
POS0009 LYMPH NODES AND PERIPHERAL BLOOD HARBOR EXPANDED T CELL RECEPTOR CLONES DURING THE PRECLINICAL PHASE OF RHEUMATOID ARTHRITIS WHICH PERSIST ON ARTHRITIS ONSET
Authors: D. Anang, G. Balzaretti, A. Olivieri, A. Al-Soudi, I. Niewold, J. F. Semmelink, B. Van Schaik, A. Van Kampen, D. Gerlag, P. P. Tak, M. G. H. Van de Sande, L. Van Baarsen, N. De Vries
Journal: Annals of the Rheumatic Diseases (2023)

<h3>Background</h3> Immunological and genetic studies implicate T cells in the initiation and progression of rheumatoid arthritis (RA) [1]. Additionally, the diversity of the T cell repertoire is known to be reduced in RA, suggesting an enrichment of disease related clonal signatures [2]. <h3>Objectives</h3> To study whether changes in the T-cell receptor repertoire (TCR) in lymph node (LN) and peripheral blood (PB) precede the onset of arthritis in seropositive at-risk individuals. <h3>Methods</h3> Unique molecular identifier (UMI)-based RNA sequencing of the TCRβ repertoire in LN biopsies and PB was performed in 9 healthy controls and 26 IgM-RF and/or ACPA positive at-risk individuals. Six of these individuals developed arthritis (RA) during at least 3 years of follow-up. PB and LN biopsies were analyzed during the at-risk phase and at RA onset. <h3>Results</h3> The TCRβ repertoire in LNs of autoantibody positive at-risk individuals harbors expanded TCRβ clones which can hardly be found in LNs of healthy controls. Regardless of whether the at-risk individuals developed arthritis or not, expanded TCRβ clones in LNs could be retrieved in peripheral blood. On RA onset, the LNs showed a marked decrease in the diversity of their TCRβ repertoire and, expanded TCRβ clones present during the at-risk phase could still be found in lymph nodes on arthritis onset. <h3>Conclusion</h3> Expanded TCRβ clones are present in lymph nodes and peripheral blood of individuals at risk of developing RA which can be retrieved in peripheral blood. Expanded TCRβ clones present in LNs during the at-risk phase persist on arthritis onset. Our analyses show a clear decrease in the diversity of the TCRβ repertoire towards onset of RA, implicating a key role for T-cell adaptive responses in steering onset of seropositive RA. <h3>References</h3> [1]Cope, A.P., <i>T cells in rheumatoid arthritis.</i> Arthritis Research &amp; Therapy, 2008. <b>10</b>(1): p. S1. [2]Jiang, X., et al., <i>Comprehensive TCR repertoire analysis of CD4+ T-cell subsets in rheumatoid arthritis.</i> Journal of Autoimmunity, 2020. <b>109</b>: p. 102432. <h3>Acknowledgements:</h3> NIL. <h3>Disclosure of Interests</h3> None Declared.
POS0462 CLINICAL PARAMETERS AFFECTING QUALITY OF LIFE IN PATIENT WITH RHEUMATOID ARTHRITIS
Authors: I. Yoshii
Journal: Annals of the Rheumatic Diseases (2023)

<h3>Background</h3> Under the treat-to-target strategies, patient with rheumatoid arthritis (RA) has achieved clinical remission in a major population, however, the impact on the quality of life remains controversial. The relationship between quality of life and disease activity control, pain control, and functional capacity control needs to be clarified. <h3>Objectives</h3> This study aims to clarify the influence of clinical parameters on the quality of life in patients with RA. <h3>Methods</h3> In this study, Patient with RA who was monitored with simplified disease activity index (SDAI) as a disease activity indicator, health assessment questionnaire disability index (HAQ-DI) as a functional capacity indicator, pain score using a visual analog scale (PS-VAS) as a pain grade indicator, EuroQol-5th dimension with 5 lines (EQ5D-5L) as a quality of life indicator, and measured Sharp/van der Heijde score (SHS) as a joint deformity indicator from the start of treatment (baseline) since January 2016, were recruited. Association between EQ5D-5L and other parameters such as gender, age, SDAI, PS-VAS, SHS, and HAQ-DI was statistically evaluated at baseline and at last observation, and change between the two periods using linear regression analysis with multivariate model. <h3>Results</h3> A total of 538 patients were included in the study. The female gender rate was 73.4%, and mean values at the baseline and at the last observation were 67.2 and 73.2 (age), 12.7 and 4.4 (SDAI), 49.3 and 46.4 (SHS), 35.4 and 24.5 (PS-VAS), 0.487 and 0.498 (HAQ-DI), and 0.755 and 0.825 (EQ5D-5L), respectively. All of these parameters were significantly different between the two periods. EQ5D-5L at baseline correlated significantly with HAQ-DI and PS-VAS, and their beta values were -0.604 and -0.444, respectively. EQ5D-5L at the last observation correlated significantly with SDAI, HAQ-DI, and PS-VAS at the last observation, and their beta values were -0.04, -0.623, and -0.099, respectively. When the last values of these parameters were divided by value at the baseline and the change from the baseline to the last observation, EQ5D-5L at the last observation correlated significantly with both of baseline and the change of all of SDAI, HAQ-DI, and PS-VAS, and their beta values were -0.439, -0.493, -0.143, 0.547, 0.605, and 0.139 for SDAI, HAQ-DI, PS-VAS at the baseline, and those change from the baseline to the last observation, respectively. <h3>Conclusion</h3> Quality of life in RA patients depends on disease activity control, pain control, and functional capacity. These variables could be controllable by treatment. <h3>REFERENCES:</h3> NIL. <h3>Acknowledgements:</h3> NIL. <h3>Disclosure of Interests</h3> None Declared.
POS0634 EVALUATION OF THE SAFETY SKILLS OF PATIENTS WITH BIOLOGICAL DMARDS AFTER A THERAPEUTIC PATIENT EDUCATION PROGRAM
Authors: I. Bencharif, D. Bendjenna, A. Ladjouze-Rezig
Journal: Annals of the Rheumatic Diseases (2023)

<h3>Background</h3> Biological DMARDs (bDMARDs) are well known cause a number of specific complications, including infectious ones. Patients receiving bDMARDs must know them and acquire self-care and safety skills in order to take charge of themselves in risky situations. This is only possible thanks to therapeutic patient education (TPE) programs in chronic Inflammatory arthritis such as rheumatoid arthritis (RA), spondyloarthritis (SpA) and Psoriatic arthritis (PsA). <h3>Objectives</h3> To evaluate the impact of the therapeutic patient education program "EST-RIC" on the safety skills in patients treated with bDMARDs and on clinical parameters (Disease activity scores, compliance, number of infectious events, number of treatment stops, vaccination rate). <h3>Methods</h3> Non-randomized clinical trial comparing the knowledge and safety skills between two cohorts of patients with RA, SpA or PsA receiving bDMARDs for at least three months in the day hospital center of CHU of Constantine: group TPE (patients joined the "EST-RIC" therapeutic education program) versus group TPE-naive (patients who did not wish to participate).The primary outcome was the acquisition of safety skills at 3 and 6 months measured by the Biosecure questionnaire (0-100 scale), a 55 item validated questionnaire assessing competences to deal with fever, infections, vaccination, and other daily life situations [1]. The secondary outcomes were disease activity scores (DAS 28 for RA and BASDAI for SpA) at 6 months, compliance (Morisky score), number of infectious events, number of treatment stops, vaccination rate at 12 months. <h3>Results</h3> 450 patients were included, with mean age 41,6 ± 12,1 years old; 235 (52,2%) women; 192 (42,7%) had RA; mean disease duration 9,9 ± 6,6 years, 269 (60%) received subcutaneous bDMARDs. 240 patients in group TPE versus 210 patients in group TPE-naive. The median Biosecure score was significantly higher in the group TPE than in the group TPE-naive (75.7/100 versus 57.9/100; p&lt;0.001) at 6 months (Table 1). There was a significant difference in disease activity scores: DAS28 and BASDAI, in rates of vaccination and discontinuation of treatment by forgetfulness. Regarding the observance to treatment or incidence of infectious events, there was no significant difference between the groups TPE and TPE-naive. <h3>Conclusion</h3> Safety is an important issue in the management of inflammatory arthritis treated with bDMARDs. In this trial, therapeutic patient education improves knowledge and safety skills of arthritis patient receiving bDMARDs, and disease activity scores. <h3>Reference</h3> [1]Gossec, et al. Joint Bone Spine 2013;80:471-6. <h3>Acknowledgements:</h3> NIL. <h3>Disclosure of Interests</h3> None Declared.
POS0682 IDENTIFICATION OF A DIAGNOSTIC MODEL FOR AXIAL SPONDYLOARTHRITIS IN DAILY CLINICAL PRACTICE USING A RANDOM FOREST MACHINE LEARNING APPROACH
Authors: I. Redeker, S. Tsiami, J. Eicker, U. Kiltz, D. Kiefer, I. Andreica, P. Sewerin, X. Baraliakos
Journal: Annals of the Rheumatic Diseases (2023)

<h3>Background</h3> In axial spondyloarthritis (axSpA), early diagnosis plays a key role in preventing disease progression. However, a validated diagnostic algorithm does not exist, while classification criteria are frequently misused diagnostically. <h3>Objectives</h3> To identify which decision model is being used for diagnosing patients with axSpA based on evaluations made in daily practice. <h3>Methods</h3> Complete clinical data of 399 patients who presented with chronic back pain in a specialized university clinic were retrospectively evaluated. All patients received complete rheumatologic examination. The total dataset was randomly split into training and test datasets at a 7/3 ratio. A model was built to classify patients into axSpA and non-axSpA based on the random forest algorithm, an ensemble machine learning technique which allows computing the importance of each variable in the statistical modelling process. The Mean Decrease Gini measure was used for the variable importance. The overall accuracy, sensitivity, specificity, and the area under the receiver operating characteristic (ROC) curve (AUC) in the test dataset were calculated. <h3>Results</h3> In total, 183 patients were diagnosed with axSpA and 216 with non-SpA (Table 1). In the test dataset, the model reached an accuracy of 0.9315, a sensitivity of 0.9634, a specificity of 0.8906, and an AUC of 0.9868 (Figure 1A). HLA-B27 positivity, erosion on SIJ MRI, and elevated CRP played the most important role in the statistical modelling process followed by awakening at second half of night due to back pain and bone marrow edema and fat metaplasia on SIJ MRI (Figure 1B). <h3>Conclusion</h3> Machine learning-based random forest classifier revealed a high performance in diagnosing patients with chronic back pain with axSpA and excluding patients with non-SpA using clinical, laboratory and imaging characteristics as evaluated in a daily practice scenario of a SpA-specialized clinic. External validation of the model is needed to investigate its clinical utility as a diagnostic decision support tool. <h3>REFERENCES:</h3> NIL. <h3>Acknowledgements:</h3> NIL. <h3>Disclosure of Interests</h3> None Declared.